Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula (A):

Ivacaftor was approved by FDA and marketed by vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO® in the form of 150 mg oral tablets. Kalydeco® is indicated for the treatment of cystic fibrosis in patients age 6 years and older who have a G55ID mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene.
U.S. 20100267768 discloses a process for preparation of ivacaftor, which involves the coupling of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphonic anhydride (T3P®) followed by deprotection of hydroxyl protection group and optional crystallization with isopropyl acetate. The publication also discloses the use of highly expensive coupling reagent, propyl phosphonic anhydride; which in turn results to an increase in the manufacturing cost. The process disclosed is schematically represented as follows:

Article titled “Discovery of N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a Potent and Orally Bioavailable CFTR Potentiator” by Hadida, S et. al in J. Med. Chem., 2014, 57 (23), pp 9776-9795 reports N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.

WO 2014125506 A2 discloses a process for the preparation of ivacaftor in high yield and purity by using novel protected quinolone carboxylic acid compounds as intermediates.
Article titled “Expeditious synthesis of ivacaftor” by Jingshan Shen et. al in Heterocycles, 2014, 89 (4), pp 1035-1040 reports an expeditious synthesis for ivacaftor featuring modified Leimgruber-Batcho procedure. The overall yield is 39% over six steps from commercially available 2-nitrobenzoyl chloride.
U.S. 2011/064811 discloses a process for preparation of ivacaftor, which involves condensation of 4-oxo-1,4-dihydro-3-quinolone carboxylic acid with 5-amino-2,4-di-(tert-butyl)phenol in the presence of HBTU followed by the formation of ethanol crystalate, which is then treated with diethyl ether to yield ivacaftor as a solid.

CN 103044263 A discloses a process for the preparation of ivacaftor as shown below:

U.S. Pat. No. 7,495,103 discloses modulators of ATP-binding cassette transporters such as ivacaftor and a process for the preparation of modulators of ATP-binding cassette transporters such as quinolone compounds. The process includes condensation of 4-oxo-1,4-dihydro-3-quinolone carboxylic acid with aniline in presence of 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro phosphate methanaminium (HATU) as shown:

U.S. 2011/230519 discloses a process for preparation of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid by reaction of aniline with diethylethoxymethylenemalonate at 100-110° C. followed by cyclization in phenyl ether at temperature 228-232° C. and then hydrolysis, as shown below:

U.S. Pat. No. 7,402,674 B2 discloses 7-Phenylamino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments.
U.S. Pat. No. 4,981,854 discloses 1-aryl-4-quinolone-3 carboxylic acids, processes for their preparation and anti-bacterial agents and feed additives containing these compounds.
Article titled “Ozonolysis Applications in Drug Synthesis” by Van Ornum, S. G.; Champeau, R. M.; Pariza, R. in Chem. Rev., 2006, 106 (7), pp 2990-3001 reports that ozonolysis for the synthesis of numerous interesting bioactive natural products and pharmaceutical agents.
Article titled “Safe Execution of a Large-Scale Ozonolysis: Preparation of the Bisulfite Adduct of 2-Hydroxyindan-2-carbox-aldehyde and Its Utility in a Reductive Amination” by Ragan, J. A. et. al. in Org. Proc. Res. Dev., 2003, 7 (2), pp 155-160 reports various routes to bisulfite adduct, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHSO3 to effect reduction and bisulfite formation in a single pot. The utility of bisulfite adduct is as an aldehyde surrogate in a reductive amination reaction.

The reported methods for the synthesis of ivacaftor suffered from several drawbacks such as harsh conditions, high temperature reactions and use of large excess of polyphosphoric acid and corrosive phosphoryl chloride etc. Furthermore, synthesis of ivacaftor requires use of high performance liquid chromatography (HPLC) techniques for the separation of ivacaftor and their analogues.
Therefore, development of a simple and efficient synthetic route is in urgent need. Accordingly the present inventors developed environmentally benign, cost effective and short synthetic route for the synthesis of ivacaftor and their analogues.